Project Summary/Abstract Parkinson's disease (PD) imposes a major burden on our aging population, and represents a neurodegenerative disorder that affects broad areas of the brain, but primarily manifests as a loss of dopaminergic neurons in the Substantia nigra. ?-Synuclein is thought to play a central role in PD because ?- synuclein mutations and polymorphisms are linked to PD, and because ?-synuclein containing inclusion bodies (Lewy bodies) are found neuropathologically in PD. Current data suggest that ?-synuclein promotes neurodegeneration in PD by misfolding into a toxic conformation, most likely as a microaggregate, that is deleterious to the neurons harboring the toxic ?-synuclein conformer. However, the mechanisms mediating the toxic effects of ?-synuclein remain incompletely understood. The present project proposes to investigate the mechanisms underlying ?-synuclein neurotoxicity in two specific aims, using cultured human neurons and mouse brains in situ as model systems, and focusing in particular on an understanding of the nature of ?- synuclein toxicity. The project will utilize an interdisciplinary approach with a particular emphasis on electrophysiological recordings to probe the relation of neuronal function, in particular as regards synaptic transmission, to ?-synuclein neurotoxicity. The results from these experiments will elucidate the extent and nature of ?-synuclein neurotoxicity in mouse and in human neurons.